We have previously reported that the antagonism of U-50,488H-induced antinociception in mice pretreated with ginseng total saponins (GTS) Ivas abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan (5-HTP), but not by a noradrenaline precursor, L-dihydroxyphenylalanine (L-DOPA) in the tail flick test. In the present experiments, the effect of the same GTS on the development of tolerance to U-50,488H-induced antinociception was determined. GTS inhibited the development of tolerance to U-50,488H-induced antinociception. The inhibitory effect of GTS on the development of tolerance to U-50,488H-induced antinociception was reversed by 5-HTP, but not by L-DOPA. These findings suggest that the inhibitory effect of GTS on the development of tolerance to U-50,488H-induced antinociception is dependent on serotonergic mechanisms. Key words Ginseng total saponin, U-50,488H, tolerance, serotonin.